Systems and methods to treat pain locally

ABSTRACT

Disclosed herein are systems and methods for contributing to the local treatment of pain. More specifically, the disclosed systems and methods contribute to the local treatment of pain by inhibiting the NFκB family of transcription factors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/635,637, filed on Mar. 2, 2015, which is hereby incorporated byreference in its entirety and which is a continuation of U.S. patentapplication Ser. No. 12/701,261, filed on Feb. 5, 2010 and issued asU.S. Pat. No. 8,969,397 on Mar. 3, 2015, which is a continuation of U.S.patent application Ser. No. 11/460,012, filed on Jul. 26, 2006.

FIELD OF THE INVENTION

The present invention relates to systems and methods for contributing tothe local treatment of pain. More specifically, the systems and methodsof the present invention contribute to the local treatment of pain byinhibiting the NFκB family of transcription factors.

BACKGROUND OF THE INVENTION

Pain can be divided into two types: acute pain and neuropathic pain.Acute pain refers to pain experienced when tissue is being damaged or isdamaged. Acute pain serves at least two physiologically advantageouspurposes. First, it warns of dangerous environmental stimuli (such ashot or sharp objects) by triggering reflexive responses that end contactwith the dangerous stimuli. Second, if reflexive responses do not avoiddangerous environmental stimuli effectively, or tissue injury orinfection otherwise results, acute pain facilitates recuperativebehaviors. For example, acute pain associated with an injury orinfection encourages an organism to protect the compromised area fromfurther insult or use while the injury or infection heals. Once thedangerous environmental stimulus is removed, or the injury or infectionhas resolved, acute pain, having served its physiological purpose, ends.

As contrasted to acute pain, neuropathic pain serves no beneficialpurpose. Neuropathic pain results when pain associated with an injury orinfection continues in an area once the injury or infection hasresolved. The biological basis for this type of pain that exists absentphysical injury or infection baffled scientists for many years.Recently, however, evidence has mounted that neuropathic pain is caused,at least in part, by on-going (and unneeded) activation of the immunesystem after an injury or infection has healed. See, for example,WATKINS & MAIER (2004), PAIN, CLINICAL UPDATES, 1-4.

Local immune system activation begins when damaged cells secrete signalsthat recruit immune system cells to the area. One type of recruitedimmune system cell is the macrophage. Macrophages release interleukin-1beta (“IL-1β”), interleukin-6 (“IL-6”) and tumor necrosis factor alpha(“TNFα”), pro-inflammatory cytokines heavily involved in orchestratingthe immediate and local physiological effects of injury or infection.For instance, once released, pro-inflammatory cytokines promoteinflammation (swelling and redness caused by increased blood flow to thearea which delivers recruited immune system cells more quickly) and alsoincreased sensitivity to pain (by increasing the excitability andtransmission of sensory nerves carrying pain information to the brain).Thus, pro-inflammatory cytokines are involved in the beneficialphysiological and recuperative effects of acute pain.

Normally after an injury or infection heals, the local immune systemresponse ceases, inflammation recedes and the increased sensitivity topain abates. In some individuals, however, signals that terminate theimmune system response are not effective entirely and pro-inflammatorycytokine activity in the area remains active. In these individuals,sensory nerves carrying pain information to the brain remain sensitizedin the absence of injury or infection and the individuals can experienceneuropathic pain.

Sciatica provides an example of pain that can transition from acute toneuropathic pain. Sciatica refers to pain associated with the sciaticnerve which runs from the lower part of the spinal cord (the lumbarregion), down the back of the leg and to the foot. Sciatica generallybegins with a herniated disc. The herniated disc itself leads to localimmune system activation. The herniated disc also may damage the nerveroot by pinching or compressing it, leading to additional immune systemactivation in the area. In most individuals, the acute pain and immunesystem activation associated with the injury cease once the damage hasbeen repaired. In those individuals where immune system activation doesnot abate completely, however, neuropathic pain may result.

As the foregoing suggests, inhibiting the actions of pro-inflammatorycytokines can provide an effective strategy for treating acute andneuropathic pain. Inhibiting the immune system, however, is problematicas a general treatment because it leaves an individual vulnerable toinfection and unable to repair tissue injuries effectively. Thus,treatments that inhibit pro-inflammatory cytokines throughout the bodygenerally are not appropriate except in the most extreme cases ofneuropathic pain. Other pain treatments likewise are not effective orappropriate for treating acute or neuropathic pain caused bypro-inflammatory cytokines. For example, narcotics do not treat painmediated by the pro-inflammatory cytokines because narcotics blockopiate receptors, a receptor type not directly involved in many effectsof the pro-inflammatory cytokines. A need exists, therefore, for alocally-administered pain treatment that suppresses the actions of thepro-inflammatory cytokines.

Generally, for a protein such as a pro-inflammatory cytokine to exert aneffect, the cell that will use or secrete the protein must create it. Tocreate a protein the cell first makes a copy of the protein's genesequence in the nucleus of the cell (this process is calledtranscription). Transcription factors are regulatory proteins thatinitiate the transcription process upon binding with DNA. Followingtranscription, the newly made copy of the gene sequence that encodes forthe protein (called messenger RNA (“mRNA”)) leaves the nucleus and istrafficked to a region of the cell containing ribosomes. Ribosomes readthe sequence of the mRNA and create the protein for which it encodes.This process of new protein synthesis is known as translation. A varietyof factors affect the rate and efficiency of transcription andtranslation. One of these factors includes the intracellular regulationof transcription factors.

The NFκB family is one group of transcription factors that plays anessential role in the inflammatory response through transcriptionalregulation of a variety of genes encoding pro-inflammatory cytokines(TNFα, IL-1β, IL-6), chemokines (IL-8, MIP1α), inducible effectorenzymes (iNOS and COX-2), and other molecules. Pro-inflammatorycytokines that are up-regulated by NFκB, such as TNFα and IL-1β, canalso directly activate the NFκB pathway, thus establishing anautoregulatory loop that can result in chronic inflammation and pain.Activation of NFκB pathways has been shown to be important in thepathogenesis of many chronic inflammatory diseases including rheumatoidarthritis, inflammatory bowel disease, and osteoarthritis.

Thus, NFκB pathway inhibition is an attractive therapeutic strategy forthe treatment of inflammatory and pain disorders. Effective NFκB pathwayblockade could result in lower levels of an array of molecules includingpro-inflammatory cytokines that contribute to inflammation and pain.However, because NFκB is also involved in normal cellular physiology,such as mounting an effective immune response, systemic inhibition ofthis pathway could result in serious side effects. For these reasons,minimizing systemic exposure of animals to NFκB inhibitory compounds isan important component of a safe therapeutic strategy.

SUMMARY OF THE INVENTION

Embodiments according to the present invention can treat pain throughthe local administration of one or more compounds that inhibit the NFκBpathway. Local administration of these compounds helps to preventunwanted side effects, such as immunosuppression, associated withsystemic drug administration.

Specifically, one embodiment according to the present invention is amethod of treating pain comprising administering one or more NFκBinhibiting compounds locally to a patient in need thereof. In specificembodiments, the one or more NFκB inhibiting compounds are selected fromthe group consisting of sulfasalazine, sulindac, clonidine, helenalin,wedelolactone, pyrollidinedithiocarbamate (PDTC), Calbiochem® IKK-2inhibitor VI, Calbiochem® IKK inhibitor III (also known as BMS-345541),and combinations thereof. The administering of the one or more NFκBinhibiting compounds can inhibit the production of one or morepro-inflammatory cytokines selected from the group consisting ofinterleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNFα) andinterleukin-6 (IL-6).

In accordance with the present invention, the one or more NFκBinhibiting compounds can be administered locally to the perispinalregion of the lumbar region of a spinal cord or can be administeredlocally to the epidural space or the intrathecal space of the lumbarregion of a spinal cord. These compounds can also be administeredlocally from an administration route selected from the group consistingof a catheter and drug pump, one or more local injections, polymerrelease, and combinations thereof.

Methods according to the present invention can be used to treat, withoutlimitation, acute pain, neuropathic pain, sciatica and/or radicularpain.

The present invention also includes dosing regimens. In one dosingregimen according to the present invention, the dosing regimen comprisesone or more NFκB inhibiting compounds and instructional information thatdirects the administration of the one or more NFκB inhibiting compoundsfor the local treatment of pain. In certain embodiments of the dosingregimens, the one or more NFκB inhibiting compounds directed to beadministered are selected from the group consisting of sulfasalazine,sulindac, clonidine, helenalin, wedelolactone,pyrollidinedithiocarbamate (PDTC), Calbiochem® IKK-2 inhibitor VI,Calbiochem® IKK inhibitor III (BMS-345541), and combinations thereof.

Instructional information used in accordance with the present inventioncan direct the one or more NFκB inhibiting compounds to be administeredlocally to the perispinal region of the lumbar region of a spinal cordor to be administered locally to the epidural space or the intrathecalspace of the lumbar region of a spinal cord. The instructionalinformation can also direct the one or more NFκB inhibiting compounds tobe administered locally from an administration route selected from thegroup consisting of a catheter and drug pump, one or more localinjections, polymer release, and combinations thereof.

In another embodiment of the dosing regimens according to the presentinvention, the instructional information directs the one or more NFκBinhibiting compounds to be administered for the treatment of acute pain,neuropathic pain, sciatica and/or radicular pain.

In another embodiment of the dosing regimens, the dosing regimen is partof a kit used for the treatment of pain. Kits according to the presentinvention can include one or more of: (i) an administration formgenerally; (ii) an administration form comprising a catheter and drugpump, (iii) an administration form comprising one or more syringes forlocal injections, (iv) an administration form comprising compositionsadapted for polymer release and (v) combinations thereof.

The present invention also includes compositions. In one embodiment ofthe compositions according to the present invention, the compositioncomprises one or more NFκB inhibiting compounds wherein the one or moreNFκB inhibiting compounds are directed to be administered locally forthe treatment of pain. In another embodiment of the compositions, theone or more NFκB inhibiting compounds are selected from the groupconsisting of sulfasalazine, sulindac, clonidine, helenalin,wedelolactone, pyrollidinedithiocarbamate (PDTC), Calbiochem IKK-2inhibitor VI, Calbiochem IKK inhibitor III (BMS-345541) and combinationsthereof.

Compositions according to the present invention can be directed to beadministered locally to the perispinal region of the lumbar region of aspinal cord or can be directed to be administered locally to theepidural space or the intrathecal space of the lumbar region of a spinalcord. The compositions can also be directed to be administered locallyfrom an administration route selected from the group consisting of acatheter and drug pump, one or more local injections, polymer releaseand combinations thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts a schematic representation of the NFκB activationpathway.

FIGS. 2 and 3 show the effect of the NFκB inhibitor sulfasalazine onpain sensitivity as measured by paw withdrawal latencies.

FIG. 4 shows the effect of the NFκB inhibitor sulfasalazine on painsensitivity as measured in a mechanical allodynia paradigm.

FIGS. 5A-5B show the effect of additional NFκB inhibitors on painsensitivity measured by paw withdrawal latencies and in a mechanicalallodynia paradigm.

FIG. 6 shows the effect of the NFκB inhibitor clonidine on painsensitivity as measured by paw withdrawal latencies.

DETAILED DESCRIPTION

While the sensation of pain can serve beneficial purposes, in manyinstances, such as neuropathic pain (which occurs in the absence ofinjury or infection) it does not and is highly undesirable. Problematicpain requiring treatment is believed to be caused at least in part dueto local immune activation. The local immune activation is mediatedlargely by pro-inflammatory cytokines including interleukin-1 beta(“IL-1β”), tumor necrosis factor alpha (“TNFα”) and interleukin-6(“IL-6”). Sciatica provides one non-limiting example of pain that can becaused by local pro-inflammatory cytokine activity.

As the foregoing suggests, inhibiting the actions of pro-inflammatorycytokines can provide an effective strategy for treating pain.Inhibiting the immune system, however, is problematic as a generaltreatment because it leaves an individual vulnerable to infection andunable to repair tissue injuries effectively. Thus, treatments thatsystemically inhibit pro-inflammatory cytokines throughout the body arenot appropriate except in the most extreme cases.

For a protein such as a pro-inflammatory cytokine to exert an effect,the cell that will use or secrete the protein must create it. Thus, oneavenue to inhibit the local actions of pro-inflammatory cytokines is toinhibit intracellular mechanisms that lead to their production andrelease. The NFκB family is the primary group of transcription factorsthat plays an essential role in regulating the transcription of genesencoding pro-inflammatory cytokines (TNFα, IL-1β, IL-6), chemokines(IL-8, MIP1α), inducible effector enzymes (iNOS and COX-2), and othermolecules. Thus, NFκB pathway inhibition is one attractive therapeuticstrategy for the treatment of inflammatory and pain disorders. EffectiveNFκB pathway blockade can result in lower levels of an array ofmolecules including pro-inflammatory cytokines that contribute toinflammation and pain. However, because NFκB is also involved in normalcellular physiology such as mounting an effective immune response,systemic inhibition of the pathway may result in serious side effects.For example global inhibition of the NFκB pathway in adult animals canrender them susceptible to opportunistic infections. Further, genetargeting studies in mice have shown that complete inactivation ofnearly any member of the NFκB pathway (at least during development)results in significant immune system defects and/or embryonic lethality.For these reasons, minimizing systemic exposure of animals to NFκBinhibitory compounds is an important component to a safe therapeuticstrategy for the treatment of pain.

The NFκB transcription factor family represents a group of structurallyrelated and evolutionarily conserved proteins that includes five membersin mammals: Rel (c-Rel), RelA (p65), RelB, NFκB1 (p50), and NFκB2 (p52).These molecules form functional transcription factors by complexing intohetero- or homodimers of the NFκB/Rel protein subunits. The mostprevalent form of NFκB is a heterodimer of the p65 and p50 subunits.

NFκB pathway activation (see FIG. 1) is regulated through a series ofevents. In unstimulated cells, NFκB is sequestered in the cytoplasm inan inactive form, bound to regulatory proteins called inhibitors of κB(IκB). A variety of stimuli including pro-inflammatory cytokines such asTNFα and IL-1β induce the phosphorylation of the IκB proteins (IκBα andIκBβ) at specific NH₂-terminal serine residues. The phosphorylated IκBproteins quickly become ubiquinated and degraded by the proteasome. Thereleased NFκB proteins are then able to translocate to the cell nucleusand induce the transcription of a variety of genes containing theircognate DNA binding recognition sequences.

A key step in NFκB activation described in the preceding paragraph isthe phosphorylation of the IκB proteins. This phosphorylation event ismediated by a specific protein complex known as IκB kinase (IKK). IKK iscomposed of two catalytic subunits IKKα and IKKβ, and a regulatorysubunit named NFκB essential modulator (NEMO) or IKKγ. Cells deficientin either IKKα or IKKβ retain some inducible NFκB activity suggestingtheir distinct roles in NFκB pathway activation. Conversely, in cellslacking IKKγ, NFκB activation is completely blocked upon the inductionof a variety of stimuli (including TNFα, IL-1, and lipopolysaccharide(LPS) exposure).

Regarding the use of NFκB inhibitors to treat pain, endoneuralinjections of an NFκB transcription factor decoy (at the site ofperipheral injury) have been shown to significantly reduce thermalhyperalgesia in a rat model of neuropathic pain. In this model NFκBinhibition also results in lower levels of a variety of pro-inflammatorymediators (including TNFα, IL-1β, IL-6, IFN-γ, and iNOS). Sakaue et al.,(Neuroreport. 2001, 12(10):2079). Spinal administration of NFκBinhibitors (ODN decoys and pyrrolidine dithiocarbamate (PDTC)) have alsobeen shown to significantly reduce mechanical allodynia and thermalhyperalgesia in the Complete Freund's Adjuvant (CFA) inflammatory painmodel. Lee et al., (Euro J. Neurosci. 2004, 19:3375). Further, Tegederet al., (J Neurosci. 2004, 24(7):1637) have reported that a specificIKK-β inhibitor (S1627) reduces hyperalgesia in inflammatory andneuropathic pain models (zymosan-induced paw inflammation) in rats. Inaddition, this inhibitor also reduces tactile allodynia in the chronicconstriction injury model (CCI) of neuropathic pain. These studiesdemonstrate the efficacy of NFκB pathway blockade in the treatment ofinflammatory and neuropathic pain.

Co-pending application publication number US2005/0095246A1 (“the '246application”) to which this application claims priority and which isincorporated by reference fully herein describes techniques to treatneurological disorders by attenuating the production of pro-inflammatorymediators. The '246 application describes the use of devices such aspumps/catheters and polymer-based drug depots for the local (peripheral,intrathecal, intraparenchymal) delivery of inhibitors ofpro-inflammatory mediators (including members of the NFκB pathway;IKK-α, β, and γ) to treat inflammatory disorders. Embodiments describedin the present application stem from these initial disclosures and alsoprovide novel compounds to locally inhibit NFκB in the local treatmentof pain through the local administration of these compounds.

EXAMPLES

The behavioral animal model of chronic constriction injury (“CCI”) waschosen to evaluate the efficacy of NFκB inhibitors as a pain treatment.This model may mimic pain associated with sciatica in humans. To induceCCI, each animal was anesthetized by intraperitoneal (“i.p.”) injectionof sodium pentobarbital at a dose of 60 mg/kg body weight. The animal'sright common sciatic nerve was exposed and freed from adherent tissue atmid-thigh by separating the muscle (biceps femoris) by blunt dissection.Four loose ligatures were placed 1 mm apart, using chromic gut (4-0absorbable suture, Jorgensen Laboratories Inc., Loveland, Colo.).

Example 1

Animals were randomly assigned to treatment groups and administeredcontrol or test compounds as follows: animals received either vehicle(Phosphate Buffered Saline; PBS), the protein-based TNFα inhibitor,Enbrel® as a positive control (3 mg/kg Immunex Corp., Seattle, Wash.) orsulfasalazine, a small molecule inhibitor of NFκB at a dose of 5 mg/kgor 50 mg/kg.

Animal behavioral testing was conducted on Days 7, 14 and 21 after CCI.In the thermal hyperalgesia test, animals were placed in the clearplastic chamber of a plantar analgesia instrument and allowed toacclimate to the environment for 15 minutes. After the acclimationperiod, a radiant (heat) beam source stimulus was applied to the CCIhind paw of each animal. The heat source device was set at an intensityof 50, and a maximum latency period of 15 seconds was set to preventtissue damage according to the recommendations of the instrumentmanufacturer. If a paw withdrawal occurred within the 15 second period,an automated control interrupted both the stimulus and timer, turningoff the radiant beam and recording the latency of time to pawwithdrawal. Data was analyzed using a one-way analysis of variance ateach test day.

FIG. 2 demonstrates that the protein-based pro-inflammatory cytokineinhibitor Enbrel® is effective to inhibit pain associated with CCI onall test days. NFκB inhibitors, however, were more effective atinhibiting pain associated with CCI on all test days. Specifically,animals that received vehicle showed mean paw withdrawal latencies ofabout 45%, 50% and 53% over baseline on test days 7, 14 and 21respectively. Animals that received Enbrel® showed mean paw withdrawallatencies of about 60%, 63% and 75% over baseline on test days 7, 14 and21 respectively. Animals receiving 5 mg/kg sulfasalazine showed mean pawwithdrawal latencies of about 80%, 83% and 87% over baseline while thosereceiving 50 mg/kg showed mean paw withdrawal latencies of about 74%,79% and 83% over baseline on test days 7, 14 and 21 respectively. Thisdata demonstrates that NFκB inhibition can provide an effectivemechanism to decrease pain sensitivity.

Example 2

In a subsequent study, additional lower doses of sulfasalazine wereevaluated for their effectiveness as a pain treatment using the CCImodel. Specifically, the same methods as described above were usedexcept that sulfasalazine was administered at doses of 5 mg/kg; 1 mg/kgor 0.2 mg/kg. As can be seen in FIG. 3, control animals receivingvehicle showed paw withdrawal latencies averaging an increase of about45%, 41% and 39% over baseline on test days 7, 14 and 21 respectively.Positive control animals receiving the protein-based TNFα inhibitor,Enbrel® increased paw withdrawal latencies to about 51%, 63% and 62%over baseline on test days 7, 14 and 21 respectively. Again, however,all doses of sulfasalazine increased paw withdrawal latencies on alltest days even further (to an average of between about 65% to about 85%over baseline measures on all test days), again suggesting thatsulfasalazine and NFκB inhibition can provide an effective paintreatment. Indeed, this data suggests that sulfasalazine can provide amore effective pain treatment than protein-based inhibitors such asEnbrel®.

Example 3

The ability of sulfasalazine to inhibit pain was also evaluated using adifferent sensitivity measure following CCI, namely mechanical (ortactile) allodynia. In this study, mechanical allodynia was determinedin reaction to probing with von Frey filaments (Stoelting, Wood Dale,Ill.). Mechanical sensitivity was measured on Days 8, 15 and 22following CCI by determining the median 50% foot withdrawal thresholdfor von Frey filaments using the up-down method described in Chaplan etal. (J Neurosci Methods 1994; 54:55) which is incorporated by referenceherein for its teachings regarding the up-down method. Rats were placedunder a plastic cover (9×9×20 cm) on a metal mesh floor. The area testedwas the middle glabrous area between the footpads of the plantar surfaceof the injured hind paw within the L4 innervation area. The plantar areawas touched with a series of 9 von Frey hairs with approximatelyexponentially incremental bending forces (von Frey values: 3.61, 3.8,4.0, 4.2, 4.41, 4.6, 4.8, 5.0, and 5.2; equivalent to: 0.41, 0.63, 1.0,1.58, 2.51, 4.07, 6.31, 10, and 15.8 g). The von Frey hair was presentedperpendicular to the plantar surface with sufficient force to causeslight bending and held for approximately 3 to 4 seconds. Abruptwithdrawal of the foot (paw flinching) was recorded as a response. Anyrat showing a mechanical threshold of more than 3.24 g was eliminatedfrom the study. As can be seen in FIG. 4, Enbrel® and sulfasalazine bothdecreased sensitivity in this paradigm when compared to controls,further suggesting that sulfasalazine and NFκB inhibition can provide aneffective pain treatment when administered at appropriate dosages.

Example 4

Next, the ability of other NFκB inhibitors to decrease pain sensitivityin the paw withdrawal and mechanical allodynia paradigms following CCIwere evaluated. In this study, the previously described methods for CCI,paw withdrawal and mechanical allodynia testing were followed exceptthat animals received vehicle control; 3 mg/kg Enbrel® as a positivecontrol; 20 mg/kg or 100 mg/kg pyrollidinedithiocarbamate (PDTC); 2mg/kg or 10 mg/kg sulindac; or 0.02 mg/kg or 0.1 mg/kg clonidine. As canbe seen in FIG. 5A, vehicle controls showed average paw withdrawallatencies of about 41% over baseline on all three test days. Positivecontrol animals receiving Enbrel® increased paw withdrawal latencies toan average of about 51% over baseline on all three test days. Animalsreceiving 2 mg/kg sulindac increased latencies to about 65% overbaseline on all three test days while those receiving 10 mg/kg increasedlatencies to about 65%, 81% and 75% over baseline on test days 7, 41 and21 respectively. Animals receiving 0.02 mg/kg clonidine showed anincrease in paw withdrawal latencies over baseline of about 75%-79% onall three test days and those receiving 0.1 mg/kg clonidine showed anincrease of about 78%, 60% and 61% over baseline on test days 7, 41 and21 respectively. This data suggests that NFκB inhibitors reduce painsensitivity further suggesting that NFκB inhibition can provide aneffective pain treatment. Interestingly, in this study, while PDTC didincrease paw withdrawal latencies over control levels, this compound wasnot as effective at reducing pain sensitivity as other NFκB inhibitingcompounds. This result could be a function of dose or administrationroute. Indeed, animals receiving 100 mg/kg PDTC were removed from thestudy following the second day of testing due to drug toxicity.

In the mechanical allodynia test, as can be seen in FIG. 5B, all NFκBinhibitors, (with the potential exception of PDTC), decreased painsensitivity when compared to control animals receiving vehicle orEnbrel®. Both doses of sulindac and the higher dose (0.1 mg/kg) ofclonidine most significantly decreased pain sensitivity. These compoundsdecreased pain sensitivity on days 8, 15 and 22 respectively as follows:sulindac (2 mg/kg): about 66%, 50% and 35%; sulindac (10 mg/kg): about68%, 58% and 60%; clonidine (0.1 mg/kg): about 58%, 20% and 48%. Animalsreceiving vehicle or Enbrel® showed increases between about 19% and 25%.Again, while PDTC showed some effect in decreasing pain sensitivity, theeffect was not as strong as that seen with sulindac or clonidine.Further, while the low dose of clonidine decreased sensitivity, it didnot show as strong as an effect in the mechanical allodynia test. Thisresult may indicate that the higher dose of clonidine is a moreappropriate dose for its use in the treatment of pain.

Example 5

Following the previous experiment, the effect of local doses ofclonidine on pain sensitivity was explored. Animals were administeredvehicle or test substances through a subcutaneously implanted Alzetpump. Again, the previously described methods for CCI and paw withdrawallatency measurements were followed except that in the presentlydescribed experiment animals received either vehicle control; 1 μg/hourEnbrel® as a positive control; 0.01 μg/hour clonidine; 0.05 μg/hourclonidine; or 0.25 μg/hour clonidine. As can be seen in FIG. 6, vehiclecontrols showed average paw withdrawal latencies of about 39%, 43% and47% over baseline on test days 7, 14 and 21 respectively. Animalsreceiving Enbrel® showed paw withdrawal latencies of about 45%, 60% and71% over baseline on test days 7, 14 and 21 respectively. Animalsreceiving 0.01 μg/hour clonidine showed paw withdrawal latencies ofabout 60%, 64% and 79% over baseline on test days 7, 14 and 21respectively. Animals receiving 0.05 μg/hour clonidine showed pawwithdrawal latencies of about 68%, 64% and 83% over baseline on testdays 7, 14 and 21 respectively. Animals receiving 0.25 μg/hour clonidineshowed paw withdrawal latencies of about 63%, 70% and 82% over baselineon test days 7, 14 and 21 respectively. In this study, all doses ofclonidine caused significant increases in paw withdrawal latencies onall three test days. Therefore, these results further suggest thatclonidine can provide an effective pain treatment when administeredlocally. Dosing of compounds such as clonidine can substantially reducethe systemic exposure of the drug without compromising the efficacy oftreatment. In the example given, there was a 25 fold dose reductionwithout loss of efficacy.

The disclosed invention describes the use of a therapeutic agent toblock activation of the NFκB signaling pathway to alleviate pain. Painis likely reduced by these inhibitors through their effect in reducinglevels of pro-inflammatory cytokines and other molecules involved in theinflammation response. The therapeutic agent may be a small moleculeinhibitor of NFκB pathway activation or other effective NFκB inhibitors.Non-limiting examples of potential therapeutic agents for use inaccordance with the present invention can include anti-oxidants thathave been shown to inhibit NFκB, proteasome and protease inhibitors thatinhibit NFκB, and IκBα phosphorylation and/or degradation inhibitors.Examples of such compounds include, without limitation, α-lipoic acid,α-tocopherol, allicin, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine,anetholdithiolthione, apocynin, 5,6,3′,5′-tetramethoxy7,4′-hydroxyflavone, astaxanthin, benidipine, bis-eugenol, bruguieragymnorrhiza compounds, butylated hydroxyanisole, cepharanthine, caffeicacid phenethyl ester, carnosol, β-carotene, carvedilol, catecholderivatives, chlorogenic acid, cocoa polyphenols, curcumin,dehydroepiandrosterone and dehydroepiandrosterone sulfate,dibenzylbutyrolactone lignans, diethyldithiocarbamate, diferoxamine,dihydroisoeugenol, dihydrolipoic acid, dilazep+fenofibric acid,dimethyldithiocarbamates, dimethylsulfoxide, disulfiram, ebselen,edaravone, epc-k1, epigallocatechin-3-gallate, ergothioneine, ethyleneglycol tetraacetic acid, flavonoids (crataegus; boerhaavia diffusa root;xanthohumol), γ-glutamylcysteine synthetase, ganoderma lucidumpolysaccharides, garcinol, ginkgo biloba extract, hematein,23-hydroxyursolic acid, iron tetrakis, isovitexin, kangen-karyu extract,1-cysteine, lacidipine, lazaroids, lupeol, magnolol, maltol, manganesesuperoxide dismutase, extract of the stem bark of mangifera indica I,melatonin, mulberry anthocyanins, n-acetyl-1-cysteine, nacyselyn,nordihydroguaiaritic acid, ochnaflavone, orthophenanthroline,hydroquinone, tert-butyl hydroquinone, phenylarsine oxide, phyllanthusurinaria, pyrrolinedithiocarbamate, quercetin (low concentrations),redox factor 1, rotenone, roxithromycin, s-allyl-cysteine, sauchinone,spironolactone, strawberry extracts, taxifolin, tempol, tepoxaline,vitamin C, vitamin B6, vitamin E derivatives, α-torphryl succinate,α-torphryl acetate, 2,2,5,7,8-pentamethyl-6-hydroxychromane, yakuchinoneα and β, n-acetyl-leucinyl-leucynil-norleucynal,n-acetyl-leucinyl-leucynil-methional,carbobenzoxyl-leucinyl-leucynil-norvalinal,carbobenzoxyl-leucinyl-leucynil-leucynal, lactacystine, β-lactone,boronic acid peptide, ubiquitin ligase inhibitors, bortezomib,salinosporamide α, cyclosporin α, tacrolimus, deoxyspergualin, 15deoxyspergualin, analogs of 15-deoxyspergualin,n-acetyl-dl-phenylalanine-β-naphthylester, n-benzoyl1-tyrosine-ethylester, 3,4-dichloroisocoumarin, diisopropylfluorophosphate, n-α-tosyl-1-phenylalanine chloromethyl ketone,n-α-tosyl-1-lysine chloromethyl ketone, desloratadine, salmeterol,fluticasone propionate, protein-bound polysaccharide frombasidiomycetes, calagualine, golli bg21, npm-alk oncoprotein, ly29,ly30, ly294002, evodiamine, rituximab, kinase suppressor of ras,pefabloc, rocaglamides, betaine, tnap, geldanamycin, grape seedproanthocyanidins, pomegranate fruit extract, tetrandine,4(2′-aminoethyl)amino-1,8-dimethylimidazo(1,2-α) quinoxaline,2-amino-3-cyano-4-aryl-6-(2-hydroxy-phenyl)pyridine derivatives,acrolein, anandamide, as602868, cobrotoxin, dihydroxyphenylethanol,herbimycin a, inhibitor 22, isorhapontigenin, manumycin α, mlb120,nitric oxide, nitric oxide donating aspirin, thienopyridine,acetyl-boswellic acids, β-carboline, cyl-19s, cyl-26z, syntheticα-methylene-γ-butyrolactone derivatives,2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-ylnicotinonitrile, plant compound a, flavopiridol, cyclopentones,jesterone dimmer, ps-1145,2-[(aminocarbonyl)amino]-5-acetylenyl-3-thiophenecarboxamides, 1′acetoxychavicol acetate, apigenin, cardamomin, synthetic triterpenoid,chs 828 (anticancer drug), diosgenin, furonaphthoquinone, guggulsterone,heparin-binding epidermal growth factor-like growth factor, falcarindol,hepatocyte growth factor, honokiol, hypoestoxide, γ-mangostin, garcinoneβ, kahweol, kava derivatives, ml120b, mx781 (retinoid antagonist),n-acetylcysteine, nitrosylcobalamin (vitamin B12 analog), non-steroidalanti-inflammatory drugs (NSAIDs), hepatitis c virus ns5b, pan1 (akanalp2 or pypaf2), n-(4-hydroxyphenyl) retinamide, sulforaphane,phenylisothiocyanate, survanta, piceatannol,5-hydroxy-2-methyl-1,4-naphthoquinone, pten (tumor suppressor),theaflavin, tilianin, zerumbone, silibinin, sulfasalazine, sulfasalazineanalogs, rosmarinic acid, staurosporine, γ tocotrienol, wedelolactone,betulinic acid, ursolic acid, thalidomide, interleukin-10, mollusumcontagiosum virus mc159 protein, monochloramine, glycine chloramine,anethole, anti-thrombin III, artemisia vestita, aspirin, sodiumsalicylate, azidothymidine, baoganning,e3((4-methylphenyl)-sulfonyl)-2-propenenitrile,e3((4-t-butylphenyl)-sulfonyl)-2-propenenitrile, benzyl isothiocyanate,cyanidin 3-o-glucoside, cyanidin 3-o-(2(g)-xylosylrutinoside, cyanidin3-o-rutinoside, buddlejasaponin IV, cacospongionolide β, carbonmonoxide, carboplatin, cardamonin, chorionic gonadotropin,cycloepoxydon, 1-hydroxy-2-hydroxymethyl-3-pent-1-enylbenzene, decursin,dexanabinol, digitoxin, diterpenes (synthetic), docosahexaenoic acid,extensively oxidized low density lipoprotein, 4-hydroxynonenal, fragilehistidine triad protein, gabexate mesilate, [6]-gingerol, casparol,imatanib, glossogyne tenuifolia, ibuprofen, indirubin-3′-oxime,interferon-α, licorice extracts, methotrexate, nafamostat mesilate,oleandrin, omega 3 fatty acids, panduratin α, petrosaspongiolide m,pinosylvin, plagius flosculosus extract polyacetylene spiroketal, phyticacid, prostaglandin α1, 20(s)-protopanaxatriol, rengyolone, rottlerin,saikosaponin-d, saline (low Na⁺ isotonic), salvia miltiorrhizaewater-soluble extract, pseudochelerythrine,13-methyl-[1,3]-benzodioxolo-[5,6-c]-1,3-dioxolo-4,5 phenanthridinium),scoparone, silymarin, socs1, statins, sulindac, thi 52(1-naphthylethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline),1,2,4-thiadiazolidine derivatives, vesnarinone, xanthoangelol d, yc-1,yopj, acetaminophen, activated protein c, alachlor,α-melanocyte-stimulating hormone, amentoflavone, artemisia capillaristhunb extract, artemisia iwayomogi extract, 1-ascorbic acid, antrodiacamphorate, aucubin, baicalein, β-lapachone, blackberry extract,buchang-tang, capsaicin, catalposide, core protein of hepatitis c virus,cyclolinteinone, diamide, dihydroarteanniun, dobutamine, e-73(cycloheximide analog), ecabet sodium, emodin, ephedrae herba, equol,erbstatin, estrogen, ethacrynic acid, fosfomycin, fungal gliotoxin,gamisanghyulyunbueum, genistein, genipin, glabridin, glimepiride,glucosamine sulfate, glutamine, gumiganghwaltang, heat shock protein-70,hypochlorite, interleukin-13, isomallotochromanol, isomallotochromene,vaccinia virus protein, kochia scoparia fruit, leflunomide metabolite,losartin, 5′-methylthioadenosine, momordin I, morinda officinalisextract, murr1 gene product, neurofibromatosis-2 protein, u0126,penetratin, pervanadate, β-phenylethyl and 8-methylsulphinyloctylisothiocyanates, phenytoin, platycodin saponins, polymyxin β, poncirustrifoliata fruit extract, probiotics, pituitary adenylatecyclase-activating polypeptide, prostaglandin15-deoxy-delta(12,14)-pgj(2), resiniferatoxin, sabaeksan, saccharomycesboulardii anti-inflammatory factor, sesquiterpene lactones(parthenolide; ergolide; guaianolides), st2 (interleukin-1-like receptorsecreted form), thiopental, tipifarnib, titanium, tnp-470, stingingnettle (urtica dioica) plant extracts, trichomomas vaginalis infection,triglyceride-rich lipoproteins, ursodeoxycholic acid, xanthiumstrumarium I, vasoactive intestinal peptide, HIV-1 vpu protein,epoxyquinone a monomer, ro106-9920, conophylline, mol 294, perrilylalcohol, mast205, rhein, 15-deoxy-prostaglandin j(2), antrodiacamphorata extract, β-amyloid protein, surfactant protein α, dq 65-79(aa 65-79 of the a helix of the -chain of the class II HLA moleculedqa03011), c5a, glucocorticoids (dexamethasone, prednisone,methylprednisolone), interleukin-10, interleukin-11, α-pinene, vitaminD, fox1j, dioxin, agastache rugosa leaf extract, alginic acid,astragaloside iv, atorvastatin, blue honeysuckle extract,n(1)-benzyl-4-methylbenzene-1,2-diamine, buthus martensi karsch extract,canine distemper virus protein, carbaryl, celastrol, chiisanoside,dehydroxymethylepoxyquinomicin, dipyridamole, diltiazem, eriocalyxin β,estrogen enhanced transcript, gangliosides, glucorticoid-induced leucinezipper protein, harpagophytum procumbens extracts, heat shock protein72, hirsutenone, indole-3-carbinol, jm34 (benzamide derivative),6-hydroxy-7-methoxychroman-2-carboxylic acid phenylamide, leptomycin β,levamisole, 2-(4-morpholynl) ethyl butyrate hydrochloride, nls cellpermeable peptides, 2′,8″-biapigenin, nucling, o,o′-bismyristoylthiamine disulfide, oregonin, 1,2,3,4,6-penta-o-galloyl-β-d-glucose,platycodi radix extract, phallacidin, piperine, pitavastatin, pn-50,rela peptides (p1 and p6), retinoic acid receptor-related orphanreceptor-α, rhubarb aqueous extract, rolipram, salvia miltiorrhoza bungeextract, sc236 (a selective cox-2 inhibitor), selenomethionine, sophoraeradix extract, sopoongsan, sphondin, younggaechulgam-tang, zud protein,zas3 protein, clarithromycin, fluvastatin, leflunomide, oxidized1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine,serratamolide, moxifloxacin, sorbus commixta cortex, cantharidin, cornusofficinalis extract, neomycin, omapatrilat, enalapril, cgs 25462,onconase, paeoniflorin, rapamycin, sargassum hemiphyllum methanolextract, shenfu, tripterygium polyglycosides, triflusal, hepatomaprotein, andrographolide, melittin, 1′-acetoxychavicol acetate,2-acetylaminofluorene, actinodaphine, adiponectin, nicotinamide,3-aminobenzamide, 7-amino-4-methylcoumarin, amrinone, angiopoietin-1,anthocyanins, sequiterpene lactones, artemisinin, atrial natriureticpeptide, atrovastat, avra protein, baicalein, benfotiamine, β-catenin,biliverdin, bisphenol a, bovine serum albumin, brazilian, bromelain,calcium/calmodulin-dependent kinase kinase, calcitriol, campthothecin,sutherlandia frutescens, caprofin, capsiate, carbocisteine, cat's clawbark, maca, celecoxib, germcitabine, cheongyeolsaseuptang, chitosan,ciclosporin, cinnamaldehyde, 2-methoxycinnamaldehyde,2-hydroxycinnamaldehyde, guaianolide 8-deoxylactucin, chlorophyllin,chondrotin sulfate proteoglycan degradation product, clarithromycin,cloricromene, commerical peritoneal dialysis solution, compound K,6-hydroxy-7-methoxychroman-2-carboxylic acid phenylamide,cryptotanshinone, cyanoguanidine, cytochalasin d, da-9201 (from blackrice), danshenshu, decoy oligonucleotides, diarylheptanoid7-(4′-hydroxy-3′-methoxyphenyl)-1-phenylhept-4-en-3-one,α-difluoromethylornithine, dim/13c, diterpenoids from isodon rubescensor liverwort jungermannia,4,10-dichloropyrido[5,6:4,5]thieno[3,2-d′:3,2-d]-1,2,3-ditriazine,e3330, ent-kaurane diterpenoids, epinastine hydrochloride, epoxyquinolα, erythromycin, evans blue, fenoldopam, fexofenadine hydrochloride,fibrates, fk778, flunixin meglumine, flurbiprofen, fomes fomentariusmethanol extracts, fucoidan, glycoprotein-120, gallic acid, ganodermalucidum, homeobox protein, geranylgeraniol, ghrelin, ginkgolide β,glycyrrhizin, halofuginone, helenalin, herbal compound 861, HIV-1resistance factor, hydroxyethyl starch, hydroxyethylpuerarin,hypercapnic acidosis, hypericin, interleukin 4, IKB-like proteins,imd-0354, insulin-like growth factor binding protein-3, jsh-21(n1-benzyl-4-methylbenzene-1,2-diamine), kamebakaurin, kaposi'ssarcoma-associated herpesvirus k1 protein, ketamine, kt-90 (morphinesynthetic derivative), linoleic acid, lithospermi radix, lovastatin,macrolide antibiotics, mercaptopyrazine, 2-methoxyestradiol, 6(methylsulfinyl)hexyl isothiocyanate, metals (chromium, cadmium, gold,lead, mercury, zinc, arsenic), mevinolin, monomethylfumarate,moxifloxacin, myricetin, myxoma virus mnf, ndppl, n-ethyl-maleimide,naringen, nicorandil, nicotine, nilvadipine, nitrosoglutathione,extracts of ochna macrocalyx bark, leucine-rich effector proteins ofsalmonella & shigella, omega-3 fatty acids oridonin1,2,3,4,6-penta-o-galloyl-beta-d-glucose, interferon inducible protein,p21 (recombinant), peptide nucleic acid-DNA decoys, pentoxifylline(1-(5′-oxohexyl) 3,7-dimetylxanthine, peptide yy, pepluanone,perindopril, 6(5h)-phenanthridinone and benzamide,phenyl-n-tert-butylnitrone, phyllanthus amarus extracts, proteininhibitor of activatated statl, pioglitazone, pirfenidone, polyozellin,prenylbisabolane 3, pro-opiomelanocortin, prostaglandin e2,protein-bound polysaccharide, pypaf1 protein, pyridine n-oxidederivatives, pyrithione, quinadril, quinic acid, raf kinase inhibitorprotein, rapamycin, raloxifene, raxofelast, rebamipide, rhus vernicifluastokes fruits 36 kda glycoprotein, ribavirin, rifamides, ritonavir,rosiglitazone, sanggenon c, santonin diacetoxy acetal derivative,secretory leucoprotease inhibitor, n-(p-coumaroyl) serotonin, sesamin,simvastatin, sinomenine, sirt1 deacetylase overexpression, siva-1,sm-7368, solana nigrum I, 150 kda glycoprotein, sun c8079, tanacetumlarvatum extract, tansinones, taurine+niacine, thiazolidinedionemcc-555, trichostatin α, triclosan plus cetylpyridinium chloride,triptolide, tyrphostin ag-126, uteroglobin, vascular endothelial growthfactor, verapamil, withaferin α, 5,7-dihydroxy-8-methoxyflavone,xylitol, yan-gan-wan, yin-chen-hao, yucca schidigera extract,amp-activated protein kinase, apc0576, artemisia sylvatica, bsasm,bifodobacteria, bupleurum fruticosum phenylpropanoids, ebv protein,chromene derivatives, dehydroevodiamine,4′-demethyl-6-methoxypodophyllotoxin, ethyl2-[(3-methyl-2,5-dioxo(3-pyrrol inyWamino]-4-(trifluoromethyl)pyrimidine-5-carboxylate, cycloprodigiosin hydrochloride,dimethylfumarate, fructus benincasae recens extract, glucocorticoids(dexametasone, prednisone, methylprednisolone), gypenoside xlix,histidine, HIV-1 protease inhibitors (nelfinavir, ritonavir, orsaquinavir), 4-methyl-(3-phenyl-propyl)-benzene-1,2-diamine, kwei lingko, ligusticum chuanxiong hort root, nobiletin, NF□β repression factors,phenethylisothiocyanate, 4-phenylcoumarins, phomol, pias3, pranlukast,psychosine, quinazolines, resveratrol, ro31-8220, saucerneol d andsaucerneol e, sb203580, tranilast, 3,4,5-trimethoxy-4′-fluorochalcone,uncaria tomentosum plant extract, mesalamine, mesuol, pertussis toxinbinding protein, 9-aminoacridine derivatives (including the antimalariadrug quinacrine), adenosine and cyclic amp,17-allylamino-17-demethoxygeldanamycin, 6-aminoquinazoline derivatives,luteolin, manassantins α and β, paromyxovirus sh gene products,qingkailing, shuanghuanglian, smilax bockii warb extract, tetracyclic a,tetrathiomolybdate, trilinolein, troglitazone, witheringia solanacealeaf extracts, wortmannin, α-zearalenol, antithrombin, rifampicin, andmangiferin (see http://people.bu.edu/gilmore/nf-kb/inhibitors/index.htmlwhich is incorporated by reference herein for a list of potentialinhibitors). The presently disclosed invention can be especiallybeneficial because pain patients treated with protein-based cytokineinhibitors (for example and without limitation, etanercept orinfliximab) often have immune responses directed against the recombinant(therapeutic) proteins. In the present invention, it is unlikely thatthere will be a significant immune response against a small moleculetherapeutic compound.

The present invention can be used to treat a variety of conditionsrelated to NFκB activation and pro-inflammatory cytokine responses. Forexample, embodiments according to the present invention could be used tocontribute to the treatment of without limitation, osteoarthritis,alkylosing spondylitis, psoriasis, rheumatoid arthritis (RA), sepsis anddegenerative disc disease. Further, it may be beneficial to coatimplantable medical devices such as, without limitation, stents andstent graft with small molecule NF□B pathway inhibitors.

In one embodiment according to the present invention, the therapeuticagents described herein are delivered locally in order to minimizeundesirable side effects associated with systemic delivery of theimmunosuppressive agents. When delivered to local sites containing cellsthat have a responsive NFκB pathway, the therapeutic agents can bedelivered through a device consisting of an infusion pump and acatheter. Local sites of delivery can include, but are not limited tothe nerve root, the dorsal root ganglion (DRG), and focal sites ofinflammation (containing infiltrating inflammatory cells). The distal,delivery end of the catheter can be surgically positioned in the tissuein close proximity to the targeted site (nerve root, DRG, etc).Alternatively, the distal end of the catheter may be positioned todeliver the therapeutic compound into the intrathecal space of thespinal cord. For acute therapeutic compound delivery, the proximal endof the catheter could remain outside of the patient's body and beattached to an external, refillable pump. For chronic administration ofthe compound, the proximal end of the catheter could be attached to apump implanted subcutaneously within a patient. In this case, the pumpwould be able to be periodically refilled using transcutaneous syringeinjection.

The NFκB inhibitors can be locally delivered by catheter and drug pumpsystems, delivered by direct local injection or through the use ofpolymers and/or drug-eluting stents as described in co-pending U.S.patent application Ser. No. 10/972,157 which is incorporated byreference herein. In one embodiment, a “controlled administrationsystem” including a direct and local administration system can be used.A controlled administration system can be a depot or a pump system, suchas, without limitation, an osmotic pump or an infusion pump. An infusionpump can be implantable and can be, without limitation, a programmablepump, a fixed rate pump, and the like. A catheter can be operablyconnected to the pump and configured to deliver agents of the presentinvention to a target tissue region of a subject. A controlledadministration system can be a pharmaceutical depot (a pharmaceuticaldelivery composition) such as, without limitation, a capsule, amicrosphere, a particle, a gel, a coating, a matrix, a wafer, a pill,and the like. A depot can comprise a biopolymer. The biopolymer can be asustained-release biopolymer. The depot can be deposited at or near,generally in close proximity, to a target site. Embodiments of thepresent invention also can be delivered through the use of liposomes,polyethyleneimine, by iontophoresis, or by incorporation into othervehicles, such as biodegradable or non-biodegradable nanocapsules. Thedelivery technology (drug pump or polymer formulations) can also beuseful for the delivery of small molecules directed against other genetargets for other clinical indications.

The present invention also includes kits. In one embodiment, the kits ofthe present invention comprise NFκB inhibitors of the present invention.In another embodiment, a kit of the present invention can contain one ormore of the following in a package or container: (1) one or more NFκBinhibitors of the present invention; (2) one or more pharmaceuticallyacceptable adjuvants or excipients; (3) one or more vehicles foradministration, such as one or more syringes; (4) one or more additionalbioactive agents for concurrent or sequential administration; (5)instructions for administration; and/or (6) a catheter and drug pump.Embodiments in which two or more of components (1)-(6) are found in thesame container can also be used.

When a kit is supplied, the different components of the compositionsincluded can be packaged in separate containers and admixed immediatelybefore use. Such packaging of the components separately can permitlong-term storage without losing the active components' functions. Whenmore than one bioactive agent is included in a particular kit, thebioactive agents may be (1) packaged separately and admixed separatelywith appropriate (similar or different) vehicles immediately before use,(2) packaged together and admixed together immediately before use or (3)packaged separately and admixed together immediately before use. If thechosen compounds will remain stable after admixture, however, theadmixture need not occur immediately before use but can occur at a timebefore use, including in one example, minutes, hours, days, months oryears before use or in another embodiment at the time of manufacture.

The compositions included in particular kits of the present inventioncan be supplied in containers of any sort such that the life of thedifferent components are preserved and are not adsorbed or altered bythe materials of the container. For example, sealed glass ampules cancontain lyophilized agents or variants or derivatives thereof or otherbioactive agents, or buffers that have been packaged under a neutral,non-reacting gas, such as, without limitation, nitrogen. Ampules canconsist of any suitable material, such as, without limitation, glass,organic polymers, such as, polycarbonate, polystyrene, etc., ceramic,metal or any other material typically employed to hold similar reagents.Other examples of suitable containers include, without limitation,simple bottles that may be fabricated from similar substances asampules, and envelopes, that can comprise foil-lined interiors, such asaluminum or an alloy. Other containers include, without limitation, testtubes, vials, flasks, bottles, syringes, or the like. Containers canhave one or more sterile access ports, such as a bottle having a stopperthat can be pierced by a hypodermic injection needle. Other containersmay have two compartments that are separated by a readily removablemembrane that upon removal permits the components to be mixed. Removablemembranes may be, without limitation, glass, plastic, rubber, etc.

As stated earlier, kits can also be supplied with instructionalmaterials. Instructions may be printed on paper or other substrate,and/or may be supplied as an electronic-readable medium, such as afloppy disc, CD-ROM, DVD-ROM, Zip disc, videotape, audiotape, flashmemory device, etc. Detailed instructions may not be physicallyassociated with the kit; instead, a user may be directed to an internetweb site specified by the manufacturer or distributor of the kit, orsupplied as electronic mail.

The terms “a” and “an” and “the” and similar referents used in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. Recitation of ranges of values herein is merely intended toserve as a shorthand method of referring individually to each separatevalue falling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g. “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is hereindeemed to contain the group as modified thus fulfilling the writtendescription of all Markush groups used in the appended claims.

Certain embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on these certain embodiments will become apparent tothose of ordinary skill in the art upon reading the foregoingdescription. The inventor expects skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than specifically described herein. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

Furthermore, numerous references have been made to patents and printedpublications throughout this specification. Each of the above citedreferences and printed publications are herein individually incorporatedby reference in their entirety.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

1. (canceled)
 2. A method of treating pain or inflammation, the methodcomprising: locally injecting a solid drug depot comprising clonidineand a sustained release biopolymer to an epidural space or anintrathecal space, wherein the pain comprises sciatica.
 3. The method ofclaim 2, wherein the biopolymer comprises polylactide.
 4. The method ofclaim 2, wherein the biopolymer comprises polylactide, and whereinlocally injecting the solid drug depot comprises injecting the depotthrough a needle.
 5. A method of treating pain or inflammation, themethod comprising: locally administering a solid drug depot comprisingclonidine and a biopolymer to an epidural space or an intrathecal space.6. The method of claim 5, wherein the pain comprises sciatica.
 7. Themethod of claim 5, wherein administering the solid drug depot comprisesa local injection.
 8. The method of claim 5, wherein the biopolymercomprises a sustained release biopolymer.
 9. The method of claim 5,wherein the biopolymer comprises polylactide.
 10. The method of claim 5,wherein the pain comprises sciatica, wherein the biopolymer comprisespolylactide, and wherein administering the depot comprises injecting thedepot through a needle.
 11. The method of claim 5, wherein the paincomprises sciatica, wherein the biopolymer comprises polylactide, andwherein administering the solid drug depot comprises a local injection.12. A method of treating pain or inflammation, the method comprising:locally administering a drug depot comprising clonidine to an epiduralspace or an intrathecal space.
 13. The method of claim 12, wherein thepain comprises sciatica.
 14. The method of claim 12, whereinadministering the drug depot comprises a local injection.
 15. The methodof claim 12, wherein the drug depot comprises a biopolymer.
 16. Themethod of claim 12, wherein the biopolymer comprises a sustained releasebiopolymer.
 17. The method of claim 12, wherein the biopolymer comprisespolylactide.
 18. The method of claim 12, wherein the depot is solid. 19.The method of claim 12, wherein the depot comprises a matrix or a pill.20. The method of claim 12, wherein the pain comprises sciatica, whereinthe biopolymer comprises polylactide, and wherein administering the drugdepot comprises a local injection.
 21. The method of claim 12, whereinthe pain comprises sciatica, wherein the biopolymer comprisespolylactide, wherein administering the depot comprises injecting thedepot through a needle, and wherein the depot is solid.